Systems, methods, and devices addressing the gastro-intestinal tract

ABSTRACT

Various embodiments disclosed herein relate to an implantable device, systems, and methods related thereto, that includes at least one sensor and/or therapeutic agent delivery depot. In one embodiment, the system and device include means for detecting general or specific biological agents in a subject&#39;s intestinal tract, and utilizing the information from the detection for determining the timing and content of any therapeutic treatment needed by the subject.

If an Application Data Sheet (ADS) has been filed on the filing date ofthis application, it is incorporated by reference herein. Anyapplications claimed on the ADS for priority under 35 U.S.C. §§119, 120,121, or 365(c), and any and all parent, grandparent, great-grandparent,etc. applications of such applications, are also incorporated byreference, including any priority claims made in those applications andany material incorporated by reference, to the extent such subjectmatter is not inconsistent herewith.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the earliest availableeffective filing date(s) from the following listed application(s) (the“Priority Applications”), if any, listed below (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Priority Application(s)).

PRIORITY APPLICATIONS

None.

If the listings of applications provided above are inconsistent with thelistings provided via an ADS, it is the intent of the Applicant to claimpriority to each application that appears in the DomesticBenefit/National Stage Information section of the ADS and to eachapplication that appears in the Priority Applications section of thisapplication.

All subject matter of the Priority Applications and of any and allapplications related to the Priority Applications by priority claims(directly or indirectly), including any priority claims made and subjectmatter incorporated by reference therein as of the filing date of theinstant application, is incorporated herein by reference to the extentsuch subject matter is not inconsistent herewith.

SUMMARY

Various embodiments disclosed herein relate to systems, methods, anddevices including a semi-permanently mounted device with one or moresensors and/or at least one therapeutic agent release depot. In anembodiment, the device is mounted in the gastro-intestinal (GI) tract ofa subject. In an embodiment, the device is mounted in the appendix of asubject.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a partial view of an embodiment of a tubular-like devicedescribed herein.

FIG. 2 shows a partial view of an embodiment of a cage-like structureddevice described herein.

FIG. 3 shows a partial view of an embodiment of an umbrella-likestructured device described herein.

FIG. 4 shows a partial view of an embodiment of a tent-like structureddevice described herein.

FIG. 5 shows a partial view of an embodiment of a coiled structureddevice described herein.

FIG. 6A shows a bottom view of an embodiment of a reversibly inflatablebladder device as described herein.

FIG. 6B shows a bottom view of an embodiment of a reversibly inflatablebladder device as described herein.

FIG. 6C shows a bottom view of an embodiment of a reversibly inflatablebladder device as described herein.

FIG. 6D shows a bottom view of an embodiment of a reversibly inflatablebladder device as described herein.

FIG. 7 shows a partial view of an embodiment of a tent-like devicedescribed herein.

FIG. 8A shows a side view of an embodiment of a reversibly inflatablebladder device described herein.

FIG. 8B shows a side view of an embodiment of a reversibly inflatablebladder device described herein.

FIG. 8C shows a side view of an embodiment of a reversibly inflatablebladder device described herein.

FIG. 8D shows a side view of an embodiment of a reversibly inflatablebladder device described herein.

FIG. 8E shows a side view of an embodiment of a reversibly inflatablebladder device described herein.

FIG. 9 shows optional locations for device components on variousembodiments.

FIG. 10A shows a partial view of an embodiment of a microfluidiccomponent optionally included in various embodiments of devicesdescribed herein.

FIG. 10B shows a partial view of an embodiment of a microfluidiccomponent optionally included in various embodiments of devicesdescribed herein.

FIG. 10C shows a partial view of an embodiment of a microfluidiccomponent optionally included in various embodiments of devicesdescribed herein.

FIG. 11 shows a partial view of a system described herein.

FIG. 12A shows a partial view of a depot configuration for one or moretherapeutic and/or nutraceutical agent reservoirs.

FIG. 12B shows a partial view of a depot configuration for one or moretherapeutic and/or nutraceutical agent reservoirs.

FIG. 12C shows a partial view of a depot configuration for one or moretherapeutic and/or nutraceutical agent reservoirs.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

Various embodiments disclosed herein relate to systems, methods, anddevices including a semi-permanently mounted device with one or moresensors and at least one actuator operably coupled to at least onetherapeutic agent and/or nutraceutical agent release depot. In anembodiment, the device is mounted in the gastro-intestinal (GI) tract ofa subject. In an embodiment, the device is mounted in the appendix of asubject. In an embodiment, the device is inserted into the subject's GItract by a health care worker (e.g., during a colonoscopy). In anembodiment, the subject has previously had its naturally occurringappendix removed, and the device disclosed herein functions as a“synthetic” or “artificial” appendix. In an embodiment, the device ismounted in the cecum of the subject. In an embodiment, the device ismounted in a gastric bypass anastomosis, or a cavity formed by surgicalresection.

The average human appendix can range from about 2 cm to about 20 cm inlength, and is usually from about 7 mm to about 8 mm in diameter. Anappendix can also be found in various other animals, including but notlimited to, other primates, opossum, wombat, rodents, and others.

Various other animals (e.g., herbivores including cows, dogs, andothers) have a cecum, that varies in size, depending on the animal. Thececum in most animals contains various types of bacteria for colonizingthe GI tract for both digestion as well as pathogen control and/orimmune surveillance.

The appendix includes gut associated lymphoid tissue, which is alsofound elsewhere in the GI tract and provides immune function. Forexample, the gut associated lymphoid tissue provides a haven for usefulbacteria, cell signaling molecules, and immune system cells (e.g.,lymphocytes such as T cells and B cells; plasma cells; and macrophages),similarly to the thyroid, breast, lung, salivary glands, eye, skin,tonsils, adenoids, Peyer's Patches, and other lymphatic organs.

In an embodiment, the device and system set forth herein include meansfor manipulating at least one component of the gut associated lymphoidtissue (GALT). In an embodiment, the device includes at least onetherapeutic agent or nutraceutical agent that binds to at least aportion of the mucosal adressin MAdCAM-1 or a receptor thereof. In anembodiment, the device includes at least one therapeutic ornutraceutical agent that binds to IgA (e.g., IgA1, IgA2, etc.). In anembodiment the device includes a therapeutic agent or nutraceuticalagent that binds at least one of a subject's chemokine, cytokine,lymphocyte, antibody, M cell, natural killer cell, or microorganism. Inan embodiment, the device includes at least one therapeutic agent ornutraceutical agent that binds to at least a portion of at least one ofL-selectin, CLA, E-selectin, or VCAM-1.

The GALT in humans is an important early site for human immunodeficiencyvirus (HIV) replication and severe CD4+ T cell depletion, however inpatients that receive highly active antiretroviral therapy (HAART), theCD4+ T cell restoration is incomplete, as is viral suppression (whencompared to peripheral blood). See Guadalupe, et al., J. Virol., Vol.80, No. 16, August 2006, which is incorporated herein by reference. Inan embodiment, the device disclosed herein includes a therapeutic ornutraceutical agent conducive to reducing HIV infection or for boostingT cell restoration or sustenance in the GALT of a subject. For example,the one or more therapeutic or nutraceutical agents can include at leastone anti-retroviral drug, anti-inflammatory agent, cytokine, chemokine,biological cell (e.g. blood cell, stem cell, fungal or bacterial cell,etc.), vitamin (e.g., vitamin C, vitamin D, vitamin E, vitamin A, betacarotene, etc.), mineral (e.g., zinc, potassium, sodium, etc.), fat,protein (including amino acids, enzymes, etc.), sugar (e.g., glucose,sucrose, fructose, simple chain sugars or complex sugars, etc.),insulin, chemotherapy agents, anti-viral agents (includinganti-retroviral agents), anti-fungal agents, or other therapeutic ornutraceutical agent for assisting in HIV infection in a subject.

In an embodiment, a system and related device are mounted in theappendix lumen of a subject. In an embodiment, the device includes atleast one housing unit. In an embodiment, the housing unit includes atleast one permeable, semi-permeable, or impermeable membrane (dependingon the full configuration of the device, see Figures for more details).In an embodiment, the membrane provides for containment of theelectronic and other components of the device. In an embodiment, one ormore electronic or other components is includes on an external side ofthe membrane of the device.

In an embodiment, the housing unit further includes at least one rigidor semi-rigid frame for support of the membrane. In an embodiment, therigid or semi-rigid frame includes at least one configuration including,but not limited to, coil, tent, square, triangle, pentagon, hexagon,octagon, decagon, etc. depending on the alignment and spacing of therigid frame components. See Figures for further details.

In an embodiment, at least one portion of the rigid or semi-rigid frameincludes a collapsible or “breakable” portion that allows for the entiredevice to be collapsed if needed or desired. For example, a breakableportion can include a weakened place on the rigid or semi-rigid frame, anotched leg, a collapsible leg, or similar “break-away” mechanism thatpassively or actively allows for collapse of the rigid or semi-rigidframe. In an embodiment, upon one or more sensors of the devicedetecting inflammation (e.g., by detecting IL-4, an increase intemperature, or an increase in white blood cells, etc.) the device willoptionally verify that it should collapse (either with an externaldatabase, an internal checking system, or command from the user), and itwill collapse for expulsion from the GI tract.

In an embodiment, the device includes at least one therapeutic agentdelivery depot. In an embodiment, the therapeutic agent delivery can beopen loop, for example, by a schedule, by continuous elution ordiffusion, or by external command (e.g., remote control). In anembodiment, the therapeutic agent delivery can be closed loop, forexample, based on an input from one or more sensors. In an embodiment,the one or more sensors are configured for monitoring at least one GItract condition (e.g., temperature, pH, motion, strain/dimensions,inflammation, bacterial type or number of one or more populations,presence/type/motion of food or fluid, etc. Such monitoring can include,in an embodiment, terminal ileum flora monitoring, nutritionalmonitoring, neoplastic cells, verification of drug metabolites tomonitor enteral passage or even compliance or other samples of interest.In an embodiment, a level sensor is utilized to tell when the reservoiris empty. In an embodiment, strain and pressure sensors are either forcases where the bladder is the depot (will indicate when it becomesempty), or tell when the bladder is too inflated or pressing too hard ontissue.

In an embodiment, one or more sensors include optical sensors that areconfigured for measuring opacity or scattering in the GI tract. In anembodiment, a light source in the appendix senses reflections, and twocomponents (e.g., one in the appendix and one in another GI location)measures transmission or scattering. In an embodiment, one or moresensors can measure conductivity or permittivity of the GI tract fluid.In an embodiment, one or more sensors include ultrasound, that allowsfor measuring of opacity, scattering, or velocity (e.g., via Doppler) inthe GI tract. In an embodiment, detection includes a cross-channelcomponent.

In an embodiment, the housing unit includes one or more reversiblyinflatable bladders utilized as “bumpers,” that, when inflated, act asintestinal wall-attachment components to secure the device between thewalls of the appendix by outward pressure. In an embodiment, a switch isoperably coupled to at least one actuator that is operably coupled tothe one or more reversibly inflatable bladders and upon activation, willdeflate the “bumpers” in whole or in part. In an embodiment, thedeflation is only partial, for example to allow movement of fluid orother biological material through or around the device, to decrease anyinflammation, or relieve pressure in the appendix. In an embodiment, thedeflation is complete and the device is collapsed and actively orpassively expelled from the appendix (and carried through the intestinaltract and out of the subject's body). In an embodiment, the deflationevent is performed when the device has exhausted itself (e.g., sensor ortherapeutic agent depot is depleted), when the device has malfunctioned,or if the appendix becomes inflamed.

In an embodiment, the switch includes an electromagnetic switch (relay)that is activated when a signal is received. In an embodiment, thesignal includes a wireless signal. Thus, in an embodiment, the device isremotely controlled such that when a signal is sent to deflate thedevice, the switch activates one or more actuators that deflate thedevice and allow for expulsion from the appendix. In an embodiment, thedevice can be induced to release at least a portion of the one or moretherapeutic or nutraceutical agent by way of a wireless signal. Thus,the device, in an embodiment, the device can be turned on and off by wayof remote control. For example, the one or more reservoirs containingthe at least one therapeutic agent or nutraceutical agent include, in anembodiment, a titanium and/or platinum seal. Passing an electric currentthrough the seal form an internal battery melts the seal, thus allowingfor a dose to diffuse out of the reservoir. See Kinkead, MIT Tech. Rev.,Jul. 4, 2014, accessed online Jul. 25, 2014 at the worldwide web andtechnologyreview.com/news, the content of which is incorporated hereinby reference.

In an embodiment, one or more electronic control units are operablyconnected to the one or more reversibly inflatable bladder “bumpers”that regulate (optionally in real-time) the level of inflation/deflationof the device, and thus adjust the pressure that the device exertsagainst the walls of the appendix. In an embodiment, the one or moreelectronic control units are regulated by one or more signals from oneor more sensors of the device.

In an embodiment, one or more reversibly inflatable bladder “bumpers”are arranged in a configuration for optimal mounting in a particularsubject's GI tract (e.g., appendix), or to fulfil a specific purpose.For example, one or more reversibly inflatable bladder “bumpers” canform extension tube rows, columns, zig-zags, circles (includingconcentric circles), “S” shape, squares, triangles, rectangles, or anycombination of these. Likewise, in an embodiment, two or more inflatablebladder “bumpers” can be spaced apart at various distances, depending onthe desired configuration and/or purpose. In an embodiment, the one ormore reversibly inflatable bladders are configured to form a helicaldevice for insertion into the subject's body. See Figures for details.

In an embodiment, the one or more reversibly inflatable bladder“bumpers” are integrally formed as an extension tube of a single bladdersuch that the increased pressure of inflating the bladder providesfeedback (e.g., to one or more sensors) as to how much the bladder is orshould be inflated. See Figures for details. In this way, in anembodiment, the reversibly inflatable bladder is able to self-regulatevolume of the bladder. In an embodiment, the reversibly inflatablebladder is self-inflating. Various modes of self-inflating bladders canbe adapted for use with one or more embodiments described herein. Forexample, inserting the device into a subject's body can cause aninternal rigid frame to which empty (deflated) bladders are affixed tocreate a physical space within the frame, such that a vacuum isgenerated and air is taken in (e.g., by way of the inlet valve) to fillthe space. Upon pressure equalization, the self-inflating bladder stopsinflating and the valve can be closed. In an embodiment, the reversibleinflatable bladder utilizes a combination of self-inflating and externalinflating (e.g., pump, pressure or temperature differential driven,etc.).

In an embodiment, the device includes at least one inflatable bladderthat is irreversible. For example, in an embodiment an inner lininginflatable bladder.

In an embodiment, the reversibly inflatable bladder is in a collapsedstate prior to, during, or after positioning into a subject's appendix.In an embodiment, the reversibly inflatable bladder is inflated before,during, or after positioning of the device into a subject's appendix. Inan embodiment, the device is positioned in a subject's appendix whilethe bag is in a collapsed state and inflated once the bag is positionedsecurely in the subject's appendix. Various means for securing thedevice in the subject's appendix are described herein. In an embodiment,the bag is inflated by way of a small cartridge of gas or a small pumpwithin the device itself. In an embodiment, the bag is inflated by wayof a tube or other means external to the subject's body. In anembodiment, the device includes a valve operably coupled to the bag.

In an embodiment, the reversibly inflatable bladder includes a flexiblematerial and optional rigid fame. In an embodiment, one or moreactuators are operably coupled to the rigid frame. In an embodiment, theone or more actuators operably coupled to the rigid frame are coupledwith control circuitry. In an embodiment, the one or more actuators areconfigured to collapse the rigid frame upon command via the controlcircuitry. In an embodiment, the command to collapse the rigid structureis transmitted by at least one of remote control, as a result of directsensor feedback, based on a timed schedule, or as a result of indirectlyby way of determination by associated circuitry based on sensor derivedinformation. In an embodiment, the control circuitry is housed withinthe reversibly inflatable bladder of the device, and upon externalcommand, or internal command, the electronic components are extrudedfrom the device. In an embodiment, the extrusion of the electroniccomponents occurs before, during, or after collapse of the rigid frame.See Figures herein.

As described elsewhere herein, the system includes a control systemoperably coupled to at least one of the various sensors describedherein, and/or at least one actuator. In an embodiment, the controlsystem is wirelessly operably coupled to at least one sensor and/or atleast one actuator. In an embodiment, the control system is operablycoupled to at least one sensor and/or at least one actuator by way of awired connection.

In an embodiment, the control system further includes control electricalcircuitry configured to direct at least one actuator or other regulatorycomponent by way of one or more signals, responsive to at least onesensing signal from at least one sensor. In an embodiment, the controlsystem includes a power supply (e.g., battery, etc.) for powering atleast some of the components of the system, for example the controlelectrical circuitry, at least one sensor, and/or at least one actuator.

In an embodiment, instructions directing the control electricalcircuitry of the control system that controls the operation of at leastone sensor and/or at least one actuator can be programmed by the subjector third party (e.g., healthcare worker, non-medical care giver,computer, etc.), or pre-programmed in the control electrical circuitry.In an embodiment, the programming of the control electrical circuitry iscarried out by at least one of software, firmware, logic devices, etc.

In an embodiment, the control electrical circuitry directs one or morecomponents of the system to operate (e.g., to allow a reversiblyinflatable bladder to inflate or deflate, to allow a collapsible jointto collapse, to allow for release of at least one therapeutic and/ornutraceutical agent, etc.), in response to at least one sensor thatsenses one or more physiological parameters of the subject, or one ormore parameters of operation of the device or system itself.

In an embodiment, the system includes memory operably coupled to thecontrol electrical circuitry and a user interface that the subject, ahealthcare worker, or other non-medical care giver utilizes to programthe operation of the system and/or device. See Figures for details. Inan embodiment, the memory can be programmed by the user interface sothat instructions for the operation of the system are stored therein. Inan embodiment, a user interface includes a keyboard, mouse, touchscreen, monitor, voice command recognition, iris scan, fingerprint scan,or other interactive device that is operably coupled to the controlelectrical circuitry of the control system. In this manner, in anembodiment the system can be programmed into memory with instructions asneeded or desired. In an embodiment, the memory is configured to storesensed data corresponding to at least one sensed signal from at leastone sensor, and can be optionally downloaded by the subject or anotherparty for analysis or decision-making.

In an embodiment, a method includes invoking an action in the system,responsive to sensing at least one parameter of the subject or oneparameter of operation of the device via at least one sensor. Forexample, in an embodiment, a sensor detects blood glucose levels whichtriggers release of glucose or insulin, as needed. In another example, asensor detects that one of the therapeutic/nutraceutical reservoirs hasmalfunctioned and triggers a shut down of that reservoir and/or depot,and optionally sends a signal to the user or another party (e.g.,healthcare worker, computer system, non-medical care giver, etc.).

In an embodiment, the method includes receiving input from at least onesensor of the system. In an embodiment, at least one component of thesystem is responsive to receiving input and/or responsive to anoperational program of the control system to drive the necessarycomponents.

In an embodiment, the method includes transmitting input from at leastone sensor of the system. In an embodiment, the method includesproviding output from at least one sensor of the system to another party(e.g., subject, computer, healthcare worker, non-medical care giver,etc.).

In an embodiment, one section of the device communicates with anothersection of the device by way of the various electronic and/or mechanicalcomponents described herein. For example, the inner surface of thedevice can provide feedback from sensors located there to the depot fordispensing of an agent, or for increasing inflation in the reversiblyinflatable bladder (if one is present).

In an embodiment the device includes an inlet valve for inflating thereversibly inflatable bladder. In an embodiment, the device includes arelease valve for rapid deflation of the reversibly inflatable bladder.In an embodiment, the device further includes means for expeditingexpulsion of the device from its location (e.g., appendix) in thesubject's body. In an embodiment, the device further includes a pumpingmeans for inflating the reversibly inflatable bladder. In an embodiment,the device includes one or more means for mobility, which may bepre-programmable and/or controllable by way of remote control.

In an embodiment, the rigid frame and/or reversibly inflatable bladderis shaped to fit the size of the subject's appendix. For example,various sizes of rigid frames can be employed, and the reversiblyinflatable bladder can be inflated or deflated in order to provide acustom fit (e.g., based on sensors on the surface or inside of thedevice that sense external contact or pressure from the subject'sappendix that provides feedback to the device with regard to level ofinflation of the bag).

In an embodiment, a controller is operably coupled to the reversiblyinflatable bladder, with at least one setting for determining athreshold range outside of which the bag inflates or deflates (orattempts to do so). In an embodiment, one or more sensors are operablycoupled to the reversibly inflatable bladder and are configured tomeasure the tension of the bag in order for the controller to determinewhether the device is operating with the bag at the proper inflationlevel. In an embodiment, the inflation/deflation bag includesprogrammable control circuitry configured for one or more pre-programmedlevels of inflation in the inflation/deflation bag. In an embodiment,the inflation/deflation bag is under the control of a remote control.

In an embodiment, the device and system include one or more sensors thatprovide feedback for operation of the device, delivery of one or moretherapeutic agents, or provide information to an entity (e.g., a remotecomputing system or device, a healthcare worker, the subject itself, adatabase or network, or other entity). In an embodiment, the one or moresensors detect, for example, contractions or expansion of the device,pressure, temperature, pH, components in the blood or GI tract fluid,etc. In an embodiment, the information received from the one or moresensors is sent to a controller to regulate the one or more inflatablebladders or release from a therapeutic or nutraceutical agent depot, orother operation of the device.

In an embodiment, the device includes one or more transmitters,receivers, or transceivers for wirelessly transmitting and receivingreports to and from an entity, as described herein. In an embodiment,the one or more sensors provide feedback relating to the operation ofthe device or system, for example with regard to one or more ofelectrical stimulators, therapeutic or nutraceutical agent dispensing,etc.

In an embodiment, the device includes one or more drainage channelsthrough or across the device (e.g., laterally, longitudinally,helically, or transversely). In an embodiment, the drainage channel islocated as an interior lumen. See the Figures for details. In anembodiment, one or more sensors is located within at least one of theone or more drainage channels.

In an embodiment, one or more microfluidic or nanofluidic chips arelocated on the housing unit of the device, or in the one or moredrainage channels. In an embodiment, the drainage channels themselvesoperate as fluidic detection components (e.g., with one or more sensorslining the drainage channels for detection of one or more analytes). Thesame is only briefly discussed herein, as one of skill in the art canappreciate that various examples can be modified or adapted for useherein as described for various embodiments.

In an embodiment, at least one of the one or more drainage channels areutilized operationally as a flow channel for a microfluidic device,while others provide mere drainage of fluid through or away from thedevice. In an embodiment, the flow channel includes an inlet, and anoutlet coupled to either end of the flow channel. In an embodiment,thermal conductors, valves, pumps (peristaltic, piezo-electric,electro-osmotic, pressure pumps, etc.), stop-flow junctions, or othermeans are included to assist in the proper flow control through thechannels. In an embodiment, the drainage channel designed to be part ofa microfluidic device, may have any shape and length provided that atleast one section thereof allows for flow of the fluid from the GI tract(e.g., digestive juices, blood, bacterial mixtures, etc.) to flowthrough one or more chambers (e.g., a chamber with a sensor, a reactionchamber for allowing the fluid to react with one or more testingcomponents, a mixing chamber for mixing the fluid if needed, andmeasuring chamber for measuring at least one property of the fluid, ifneeded), adaptable to the device depending on the size, structure, andpurpose. In an embodiment, the flow channel includes at least onedimension (e.g., length, diameter, a maximum dimension for example ifinflated, etc.) of at least about 1 nanometer, at least about 10nanometers, at least about 20 nanometers, at least about 50 nanometers,at least about 100 nanometers, at least about 10 micrometers, at leastabout 20 micrometers, at least about 50 micrometers, at least about 100micrometers, at least about 200 micrometers, at least about 300micrometers, at least about 400 micrometers, at least about 500micrometers, or any value therebetween.

In an embodiment, the microfluidic portion of the device includes atleast one flow control channel section. In an embodiment, the flowcontrol channel section has a length that is at least about 2 times, atleast about 3 times, at least about 4 times, at least about 5 times, atleast about 10 times, at least about 15 times, at least about 20 times,or any value therebetween, longer than the fluid flow channels. In anembodiment, the flow control channel section is at least about 90%, atleast about 95%, at least about 99% smaller than the average crosssectional area of the fluid flow channel section (e.g., drainagechannel, if used for this purpose).

In an embodiment, the one or more sensors include at least one sensor inthe GI tract. In an embodiment, the one or more sensors include at leastone remote sensor (e.g. located elsewhere in the subject's body, locatedexternal to the subject's body, located in the room where the subjectresides, etc.). In an embodiment, the one or more sensors include atleast one sensor that is configured to reversibly extend into the GItract. As described herein, the one or more sensors may be configured tomeasure at least one of temperature, pH, motion, strain/dimensions,inflammation, bacteria or other microorganisms that make up a microbiomeor represent potential infection, presence or motion of food in the GItract, etc. In an embodiment, the one or more sensors allow forsurveillance of one or more of terminal ileum flora, nutritionalmonitoring, neoplastic cells, verification of drug metabolites forenteral passage or compliance, or samples of interest along the GItract.

In an embodiment, the device is inserted by catheter into the subject'sbody (e.g., downward from the throat, upward from the rectum, etc.). Inan embodiment, the device is inserted into the subject's body by way ofself-mobile device (e.g., orally swallowed as it travels downward, orcolon crawlers that allow for it to travel upward to the GI tract,etc.).

In an embodiment, at least one therapeutic agent is dispensed from thedevice and system, and provides therapeutic treatment for one or more ofulcerative colitis, celiac disease, inflammatory bowel disease, generalinflammation of the GI tract, food poisoning or other GI tract infection(appendicitis, etc.), or other GI related condition. In an embodiment,the therapeutic agent provides a preventative agent to the GI tract(e.g., probiotics, vitamins, minerals, other nutraceuticals, etc.). Inan embodiment, the nutraceutical agent includes at least one of vitaminA, D, C, E.

In an embodiment, at least one component of the device (e.g., thehousing unit) includes an anti-inflammatory agent (e.g., ananti-inflammatory material or chemical coating) in order to reducepotential inflammation reactions with the device. In an embodiment, thehousing unit is fabricated from or includes anti-inflammatory magnesiumhydroxide nanoparticles incorporated into poly (D, L-lactic-co-glycolicacid) (PLGA) scaffolds with various porogen materials. For example,freeze drying such a preparation results in lowered IL-6 expression, abiomarker for inflammation. See for example, Lee, et al., MacromolecularResearch, February 2014, Vol. 22, No. 2, pp. 210-218, which isincorporated herein by reference.

Likewise, housing units fabricated at least in part frommagnesium-zinc-silver biomaterials exhibit good cytocompatibility andanti-inflammatory properties, and can be adapted for use with variousembodiments disclosed herein. See for example, Peng et al., J. Biomed.Mat. Res. Pt. A, Dec. 3, 2012, Abstract, which is incorporated herein byreference.

In an embodiment, the housing unit is fabricated at least in part withfar-infrared ray-emitting ceramic materials (bioceramics), which havebeen shown to promote microcirculation and anti-inflammatory properties,and can be adapted for use with various embodiments disclosed herein.See Leung et al., J. Med. and Biol. Eng., 33(2):179-184, 2011, which isincorporated herein by reference.

In an embodiment, the housing unit is fabricated at least in part of oneor more biodegradable polymers (e.g., poly(lactide), polyglyconate,polyanhydrides, polyorthoesters, or poly(glycolide)). In an embodiment,at least one therapeutic or nutraceutical agent is delivered at a rateequal to the degradation of the device itself. In addition, the deviceincludes biodegradable or bioresorbable electronic components (e.g.,cocoon silk, etc.) as well.

In an embodiment, the housing unit includes at least one of a mesh orsemi-permeable membrane that sits adjacent to the lumen wall in thesubject's GI tract. In an embodiment, the device includes at least onearray of mechanical or chemical “feet” between the housing unit and thelumen wall for support. See Figures for details. In an embodiment, thechemical feet include gel or other polymer protrusions from the housingunit.

In an embodiment, the device is preloaded for a single use. In anembodiment, the device is refillable. In an embodiment, the device canbe refilled via catheters, pills, etc. In an embodiment, the deviceincludes at least one reversibly inflatable bladder as described herein,wherein the bladder includes a valve (e.g., at the front of the device)that allows the device to be inflated by injection of fluid (e.g., gas,liquid, gel, etc.) which may include a therapeutic agent. In anembodiment, the device includes two or more therapeutic or nutraceuticalagent depots, as described herein. In an embodiment, each of the two ormore therapeutic or nutraceutical agent depots includes a differenttherapeutic or nutraceutical agent. In this manner, in an embodiment, acombination of multiple therapeutic or nutraceutical agents can bedispensed into the subject's body from the device.

In an embodiment, the device and/or system includes wirelesscommunication to report on its drug deliveries and sensed conditions, orto receive commands, as described herein. In an embodiment, the deviceis removable (e.g., via catheter, via self-collapse, via crawling out,for example by remote control).

In an embodiment, the intestinal wall-attachment component includes atleast one of a screw, suture, staple, clip, anchor, hook, brace,reversibly inflatable bladder, projection, umbrella connector, barb,latch, or adhesive.

In an embodiment, the device is sized and shaped for mounting in theappendix or other GI tract location. In an embodiment, electrodes areincluded in the device and are separated by insulating material, all ofwhich can be sealed in a segment or as part of the housing unit of thedevice. In an embodiment, the device includes a controller operablycoupled to a power source. In an embodiment, the electronic componentsare contained in part of the housing unit. In an embodiment, theelectronic components are contained in the walls of the housing unit,with the central channel or cavity of the device remaining hollow toaccommodate fluid flow. See Figures for details. In this way, in anembodiment the device should not readily induce inflammation since itallows for fluid flow through and/or around the device itself. Forexample, in an embodiment, the device may act as a stent to keep theappendix from swelling from infection and/or closing in on itself.

As shown in FIG. 1, a system 100 includes a device 105, with a rigid orsemi-rigid structure 180 and optionally with an outer membrane 110(e.g., permeable, semi-permeable, bioresorbable, or biodegradable). Inan embodiment, the outer membrane 110 does not cover the entire device(not shown). In an embodiment, the outer membrane 110 is reversiblyinflatable. In an embodiment, the outer membrane 110 is reversiblyinflatable and only covers a portion of the device, thus forming aninflatable collar. As shown in FIG. 1, a tubular device 105, allows forfluid flow 101 through the device. As shown, in an embodiment, at leastone sensor 130, transmitter 150, receiver 160, power source 140, andelectrical circuitry 170, are located on the outer side of the rigid orsemi-rigid structure 180. In an embodiment (not shown), the samecomponents are located on the inner side of the rigid or semi-rigidstructure 180. In an embodiment, as shown, a depot 120 for one or moretherapeutic agents and/or one or more nutraceutical agents is includedin the device 105. In an embodiment, the depot 120 is located on theinner surface of the device 105. In an embodiment (not shown), the depot120 is located on the outer surface of the device 105.

As shown in FIG. 2, a system 200 includes a device 205, with a rigid orsemi-rigid structure 280 and optionally with an outer membrane (notshown) (e.g., permeable, semi-permeable, bioresorbable, orbiodegradable). As shown in FIG. 2, a polymer cage-like device 205(optionally from a biodegradable polymer), allows for fluid flow 201through the device. As shown, in an embodiment, at least one sensor 230,transmitter/receiver/transceiver 240, microfluidic component 225,electrical circuitry (not shown), and collapsible joint 260 are includedin the device. In an embodiment (not shown) these components are locatedon the outer side of the rigid or semi-rigid structure 280. In anembodiment, the same components are located on the inner side of therigid or semi-rigid structure 180. In an embodiment, a depot 220 for oneor more therapeutic agents and/or one or more nutraceutical agents isincluded in the device 205. In an embodiment, the depot 220 is locatedon the inner surface of the device 205. In an embodiment (not shown),the depot 220 is located on the outer surface of the device 205. As onewill appreciate, the exact configuration of the cage-like device caninclude, for example, a square, pyramid, pentagon, hexagon, octagon,circle, oval, sphere, etc. and is not limited by number of sides orproportion of side lengths to each other, within the confines of thevarious components described herein.

As shown in FIG. 3, a system 300 includes a device 305, with a rigid orsemi-rigid structure 390 and optionally with an outer membrane 310(e.g., permeable, semi-permeable, bioresorbable, or biodegradable). Asshown in FIG. 3, an umbrella-like device 305 (optionally from abiodegradable polymer), allows for fluid flow 301 through the device. Asshown, in an embodiment, at least one sensor 330, transmitter 320,receiver 330, power source 340, light source 350, microfluidic component375, and at least one collapsible joint 370, and electrical circuitry(not shown) are included in the device. In an embodiment (not shown)these components are located on the outer side of the rigid orsemi-rigid structure 390. In an embodiment, one or more wall attachmentcomponents 380 are located such that the umbrella-like device is openedend to end upon attachment to the GI tract wall. In an embodiment, anopening 390 provides for fluid flow 301 through the device. In anembodiment, a depot 320 for one or more therapeutic agents and/or one ormore nutraceutical agents is included in the device 305. In anembodiment, the depot 320 is located on the inner surface of the device305. In an embodiment (not shown), the depot 320 is located on the outersurface of the device 305 (optionally between the structure 390 and theouter membrane 310).

As shown in FIG. 4, a system 400 includes a device 405, with a rigid orsemi-rigid structure 480 and optionally with an outer membrane 410(e.g., permeable, semi-permeable, bioresorbable, or biodegradable). Asshown in FIG. 4, a tent-like device 405 (optionally from a biodegradablepolymer), allows for fluid flow 401 through the device. As shown, in anembodiment, at least one sensor 430, power source 440, light source 450,transmitter 460, receiver 420, microfluidic component 425, and at leastone collapsible joint 470, and electrical circuitry (not shown) areincluded in the device. In an embodiment (not shown) these componentsare located on the outer side of the rigid or semi-rigid structure 480(optionally between the structure 480 and the outer membrane 410).

As shown in FIG. 5 (side view and top view), a system 500 includes adevice 505, with a rigid or semi-rigid structure 580 and optionally withan outer membrane 510 (e.g., permeable, semi-permeable, bioresorbable,or biodegradable). As shown in FIG. 5, a spiral-like or coiled device505 (optionally from a biodegradable polymer), allows for fluid flow 501through the device. As shown, in an embodiment, at least one sensor 530,power source 540, light source 550, transmitter 560, receiver 520,microfluidic component 575, and electrical circuitry 570, are includedin the device. In an embodiment (not shown) these components are locatedon the outer side of the rigid or semi-rigid structure 580.

As shown in FIG. 6A (bottom view), a system 600 includes a device 605with one or more reversibly inflatable bladders 670 with an optionalouter membrane 610 (e.g., permeable, semi-permeable, bioresorbable, orbiodegradable). As shown in FIG. 6A, a bottom view of an reversiblyinflatable bladder 670, allows for fluid flow 601 through the device. Asshown, in an embodiment, a port 650 to inflate/deflate the reversiblyinflatable bladder 670 is included. The device further includes anopening 690 that provides an inner surface to which device componentscan be adhered (see FIG. 6B). In an embodiment, a sensor 640, atransceiver 620, and a pump 630 is located on the outer surface of thereversibly inflatable bladder 670, and optionally beneath the outermembrane 610. In an embodiment, the reversibly inflatable bladder 670puts pressure on the GI tract wall 660, thereby keeping the device inplace.

As shown in FIG. 6B (bottom view), a system 600 includes a device 605with one or more reversibly inflatable bladders 670 with an optionalouter membrane (not shown) (e.g., permeable, semi-permeable, orbiodegradable). As shown in FIG. 6B, the reversibly inflatable bladder670, allows for fluid flow 601 through the device. As shown, in anembodiment, a port 650 to inflate/deflate the reversibly inflatablebladder 670 is included. The device further includes an opening 690 thatprovides an inner surface to which the device components can be adhered.In an embodiment, a sensor 640, transceiver 630, and depot 620 for oneor more therapeutic agents and/or one or more nutraceutical agents isincluded in the inner surface of the device. In an embodiment, thecomponents of the device are located at the outer surface of the device.In an embodiment, the reversibly inflatable bladder 670 puts pressure onthe GI tract wall 660, thereby keeping the device in place.

As shown in FIG. 6C (bottom view), a system 600 includes a device 605with one or more reversibly inflatable bladders 670 with an optionalouter membrane (not shown) (e.g., permeable, semi-permeable, orbiodegradable). As shown in FIG. 6C, the reversibly inflatable bladder670, allows for fluid flow 601 through the device. As shown, in anembodiment, a port 650 to inflate/deflate the reversibly inflatablebladder 670 is included. The device further includes an opening 690 thatprovides an inner surface to which the device components (not shown) canbe adhered. In an embodiment, an adhesive 695 is utilized to adhere thedevice to the GI tract wall 660, thereby keeping the device in place.

As shown in FIG. 6D (bottom view), a system 600 includes a device 605with one or more reversibly inflatable bladders 670 with an optionalouter membrane (not shown) (e.g., permeable, semi-permeable, orbiodegradable). As shown in FIG. 6D, the reversibly inflatable bladder670, allows for fluid flow 601 through the device. As shown, in anembodiment, a port 650 to inflate/deflate the reversibly inflatablebladder 670 is included. The device further includes an opening 690 thatprovides an inner surface to which the device components (not shown) canbe adhered. In an embodiment, a rigid or semi-rigid frame 680 isutilized to adhere the device to the GI tract wall 660, thereby keepingthe device in place.

As shown in FIG. 7, a system 700 includes a device 705 with a rigid orsemi-rigid structure 790 including a hinge 780 and optionally with anouter membrane 710 (e.g., permeable, semi-permeable, or biodegradable).As shown in FIG. 7, a spiral-like or coiled device 705 (optionally froma biodegradable polymer), allows for fluid flow 701 through the device.As shown, in an embodiment, at least one sensor 730, power source 740,light source 750, transmitter 760, receiver 760, microfluidic component735, and electrical circuitry (not shown), are included in the device.In an embodiment (not shown) these components are located on the outerside of the rigid or semi-rigid structure 790. In an embodiment, thecomponents are located on an inner surface of the device, or optionallyin between the rigid or semi-rigid structure 790 and the optional outermembrane 710. In an embodiment, one or more GI wall attachmentcomponents 770 are included in the device, such that the device isopened at the hinge 780 and the wall attachment components 770 keep thedevice in place in the GI tract. In an embodiment, the same componentsare located on the inner side of the rigid or semi-rigid structure 790.In an embodiment, a depot 720 for one or more therapeutic agents and/orone or more nutraceutical agents is included in the device 705. In anembodiment, the depot 720 is located on the inner surface of the device705. In an embodiment (not shown), the depot 720 is located on the outersurface of the device 705.

As shown in FIG. 8A, a system 800 includes a device 805 with one or morereversibly inflatable bladders 870 with an optional outer membrane (notshown) (e.g., permeable, semi-permeable, or biodegradable). As shown, inan embodiment, a port 850 to inflate/deflate the reversibly inflatablebladder 870 is included. In an embodiment, an adhesive 870 is utilizedto adhere the device to the GI tract wall 898, thereby keeping thedevice in place.

As shown in FIG. 8B, a system 800 includes a device 805 with one or morereversibly inflatable bladders 870 with an optional outer membrane (notshown) (e.g., permeable, semi-permeable, or biodegradable). As shown, inan embodiment, a port 850 to inflate/deflate the reversibly inflatablebladder 870 is included. In an embodiment, an expandable wall attachmentcomponent 880 is utilized to attach the device to the GI tract wall 898,thereby keeping the device in place.

As shown in FIG. 8C, a system 800 includes a device 805 with one or morereversibly inflatable bladders 870 with an optional outer membrane (notshown) (e.g., permeable, semi-permeable, or biodegradable). As shown, inan embodiment, a port 850 to inflate/deflate the reversibly inflatablebladder 870 is included. In an embodiment, a hinged wall attachmentcomponent 890 is utilized to attach the device to the GI tract wall 898,thereby keeping the device in place.

As shown in FIG. 8D, a system 800 includes a device 805 with one or morereversibly inflatable bladders 870 with an optional outer membrane (notshown) (e.g., permeable, semi-permeable, or biodegradable). As shown, inan embodiment, a port 850 to inflate/deflate the reversibly inflatablebladder 870 is included. In an embodiment, an intra-bladder port 860, isutilized to adjust the inflation levels of multiple reversiblyinflatable bladders 870. In an embodiment, a staple wall attachmentcomponent 875, a hook wall attachment component 895, or an anchor wallattachment component 885 is utilized to attach the device to the GItract wall 898, thereby keeping the device in place.

As shown in FIG. 8E, a system 800 includes a device 805 with one or morereversibly inflatable bladders 870 with an optional outer membrane (notshown) (e.g., permeable, semi-permeable, or biodegradable). As shown, inan embodiment, a port 850 to inflate/deflate the reversibly inflatablebladder 870 is included. In an embodiment, an intra-bladder port 860, isutilized to adjust the inflation levels of multiple reversiblyinflatable bladders 870. In an embodiment, a suture attachment component865 is utilized to attach the device to the GI tract wall 898, therebykeeping the device in place.

As shown in FIG. 9, various embodiments of devices 905 contacting the GItract wall 930, are shown to illustrate a particular embodiment wherethe electrical components 920 of the devices 905 are located on eachparticular device. Further details are provided in the related Figures.For example, in any of the devices 905 with an optional outer membrane910 as previously described herein, the electronic components 920 islocated at an inner surface location of the device, an outer surface ofthe device, or in between the device 905 and the outer membrane 910. Inan embodiment, the electronic components 920 include one or morecircuits 965, at least one microfluidic device 935, at least one depot955 including one or more therapeutic agents and/or one or morenutraceutical agents, at least one light source 945, one or more sensors940, at least one power source 980, at least one controller 950, atleast one transmitter 970, at least one receiver 960, wherein one ormore components is located on a microchip (as shown). In an embodiment,one or more microchips of components 920 are located in a device (e.g.,in a cluster, on a platform, in multiple locations of the device, etc.)and is not limited to any particular configuration. As shown in FIG. 10,various configurations of microfluidic devices may be employed withembodiments disclosed herein. For example, as shown in FIG. 10A, amicrofluidic device 1050 includes at least one inlet 1000 that isoperably connected to one or more channels 1040 that allows for fluidflow 1020 along the one or more channels 1040, toward the detection zone1030 and to the outlet 1010. As shown in FIG. 10B, a microfluidic device1052 includes at least one inlet 1000 operably connected to one or morechannels 1040 that allows for fluid flow 1020 along the one or morechannels 1040 toward the detection zone 1030 and to the outlet 1010. Asshown in FIG. 10C, a microfluidic device 1053 includes at least oneinlet 1000 that is operably connected to one or more channels 1040 thatallows for fluid flow 1020 along the one or more channels 1040, towardthe detection zone 1030 and to the outlet 1010.

As shown in FIG. 11, a system 1100 includes a device 1120 as describedherein, configured to send signals 1130 to and receive signals 1130 fromat least one computing system 1150. In an embodiment, at least one user1140 (e.g., healthcare worker, subject itself, parent/guardian,caretaker, etc.) who can enter information into the computing system1150 and provide directions back to the device 1120 in the subject.Alternatively, the device 1120 can access one or more databases directlyby way of engaging with the computing system 1150. For example, in anembodiment, the device 1120 is able to access the subject's own personalhealth records, family health records, or general health databases(e.g., CDC databases) by sending and receiving signals 1130 to and fromthe computing system 1150. In an embodiment, the device 1120 sendsand/or receives signals 1130 relating to the function of the deviceitself (microfluidic data, other sensor data, level of agent in one ormore depots for therapeutic and/or nutraceutical agents, battery level,or other operational status, etc.).

As shown in FIG. 12A, a depot 1200 including one or more therapeuticagents and/or one or more nutraceutical agents includes one or moretransmitters/receivers/transceivers (not shown) or utilizes thetransmitter/receiver/transceiver of the device as described herein, tosend and/or receive signals 1230 with a computing device (not shown).Thus, in this manner, the depot 1200 is able to be operated by remotecontrol. (See for example, Kinkead, MIT Tech. Rev., Jul. 4, 2014accessed online Jul. 25, 2014 at technologyreview.com/news, the contentof which is incorporated herein by reference). For example, a microchipdepot includes an outlet 1220 for the agent to pass from the depot tothe subject's body. The depot includes one or more reservoirs 1210sealed by a thin metal membrane 1215, such as platinum and titanium. SeeId. Upon activation of the device (e.g., by way of wireless signal),allows for a thin electric current to pass through the thin metalmembrane seal 1215, melting the seal temporarily and releasing the agentcontained within the one or more reservoirs 1210 of the depot.

As shown in FIG. 12B, a depot 1200 including one or more reservoirs 1250containing one or more therapeutic agents and/or one or morenutraceutical agents (as described herein, the depot can includereservoirs each with the same agent or reservoirs each with differentagents. In an embodiment, the depot includes one or moretransmitters/receivers/transceivers (not shown) or utilizes thetransmitter/receiver/transceiver of the device as described herein, tosend and/or receive signals 1230 with a computing device (not shown).Thus, in this manner, the depot 1200 is able to be operated by remotecontrol. For example, a microchip depot includes an outlet 1220 for theagent to pass from the depot to the subject's body. In an embodiment,the one or more reservoirs 1250 are inflated with the agent containedtherein and are under pressure (e.g. from the fluid pressure of theagent), and are activated (e.g., wirelessly) by operation of a valve1280 operably coupled to the reservoir 1250, which expels the agent fromthe reservoir 1280 through an outlet 1260 and into the subject's body.In an embodiment, a micropump 1270 (or microjet) is utilized to expelthe agent from the reservoir 1250 through the outlet 1240 operablycoupled to the micropump/microjet 1270 and the reservoir 1250.

As shown in FIG. 12C, a depot 1200 including one or more reservoirs 1295containing one or more therapeutic agents and/or one or morenutraceutical agents (as described herein, the depot can includereservoirs each with the same agent or reservoirs each with differentagents. In an embodiment, the depot includes one or moretransmitters/receivers/transceivers (not shown) or utilizes thetransmitter/receiver/transceiver of the device as described herein, tosend and/or receive signals 1230 with a computing device (not shown).Thus, in this manner, the depot 1200 is able to be operated by remotecontrol. For example, a microchip depot includes an outlet 1275 for theagent to pass from the depot to the subject's body. In an embodiment,the one or more reservoirs 1295 are sturdy compartments with the agentcontained therein and are under pressure (e.g. from the fluid pressureof the agent), and are activated (e.g., wirelessly) by operation of avalve 1265 operably coupled to the reservoir 1295, which expels theagent from the reservoir 1295 through an outlet 1275 and into thesubject's body. In an embodiment, a micropump or microjet (not shown) isutilized to expel the agent from the reservoir 1295 through the outlet1275 operably coupled to the micropump/microjet and the reservoir 1295.

In an embodiment, any of the reservoirs (1250, 1295, 1210) described aremanufactured with biodegradable materials, such that the reservoiritself can be absorbed by the subject's body following expulsion of thetherapeutic or nutraceutical agent(s) contained therein. In anembodiment, the depot includes multiple reservoirs, each containing adifferent agent. In an embodiment, the depot includes electricalcircuitry (not shown) that activates the reservoir directly orindirectly (e.g., wireless signal from remote control, signal fromcomputer program as part of the system described herein, or signal fromoutside of the system based on timing or feedback from at least one ofthe sensors of the medical device itself (for which the depot is acomponent). Thus, in this manner, in an embodiment the medical device is“stocked” with several therapeutic and/or nutraceutical agents beforeactivation (whether prior to insertion of the device, or subsequent toinsertion of the device in the subject's body) and delivery of the oneor more agents to the subject. In an embodiment, the depot is regulatedbased on feedback from the one or more sensors. In an embodiment, thedepot is regulated based on external commands (e.g., from a healthcareworker, computer database, computer program, timed schedule, etc.). Forexample, if a particular agent is needed for control of inflammation(e.g., in HIV infection, inflammatory bowel disease, Crohn's disease,etc.) the sensed information related to inflammation is directly orindirectly utilized to activate at least one reservoir of the depot thatcontains an anti-inflammatory agent (therapeutic or nutraceutical), andfurther feedback is obtained to track the reaction followingadministration of the anti-inflammatory agent. If additional dispensingof anti-inflammatory agents is needed, another reservoir of the depotwill be activated to release the same type or a different type ofanti-inflammatory agent.

Likewise, if a particular agent is needed to enhance one or moremicroorganisms of the subject's microbiome or GALT, that agent isreleased in response to sensed data, and the continuous or intermittentmonitoring continues, along with release of therapeutic/nutraceuticalagents as needed.

PROPHETIC EXAMPLES Prophetic Example 1 An Implantable IntestinalMedicament Delivery Device with Inflammation Sensors and a ReversiblyInflatable Anchor

An implantable medicament delivery device to prevent and mitigateinflammatory bowel disease (IBD) is constructed as a small, hollowtubular device with an inflatable collar to anchor the device in theappendix and sensors to detect markers of inflammation. The walls of thetube are hexagonal and contain depots with reservoirs containinganti-inflammatory therapeutics to treat inflammation in the gut and topromote a healthy gut associated lymphoid tissue (GALT). (See Figures).The tubular device is constructed from biocompatible materials to resideinside the appendix and to allow free flow of mucus, cells, and fluidsinto and out of the appendix through the lumen of the device. Thedevice, a hexagonal tube, is anchored in the appendix by an inflatablecollar, and extends distally into the ascending colon. The devicecontains sensors of inflammation which signal to control circuitry whichin turn initiates release of anti-inflammatories and prebiotics into thecolon.

The device is constructed with dimensions that allow insertion into thelumen of the appendix. For example the hexagonal tube is approximately 6mm in outside diameter and approximately 2 to 3 cm in length. Thehexagonal tube is formed from a biocompatible polymer, for example,polyethylene-co-vinyl acetate (PEVA) (available from Polysciences, Inc.,Warrington, Pa.; see PEVA info sheet). Methods and materials tomanufacture polymers with a desired porosity and physical properties(e.g., flexibility, tensile strength and biocompatibility) are described(see e.g., Handbook of Membrane Separations: Chemical, Pharmaceutical,Food, and Biotechnological Applications, edited by Anil K. Pabby, SyedS. H. Rizvi, Ana Maria Sastre, 2009, CRC Press, Boca Raton, Fla. whichis incorporated herein by reference). Alternatively a strong,biocompatible material that slowly degrades may be used to construct thedevice. For example poly(anhydride-co-imide) may be adapted for use (seee.g., U.S. Pat. No. 6,669,683, which is incorporated herein byreference).

The implantable device has several drug delivery reservoirs embedded inthe interior walls of the hexagonal tube. Medicaments are released intothe lumen of the device upon signaling from control circuitry whichheats thermally responsive reservoir caps. Reservoirs are created usingmicroelectronic manufacturing methods and semiconductor materials. Forexample, reservoirs 800 μm×800 μm and approximately 500 μm deep may becreated in silicon wafers using photolithography, chemical etching anddeposition technologies. Hundreds of reservoirs may be created in arrays(also referred to as depots) approximately 2 mm×30 mm on the innerhexagonal walls of the tube. The reservoirs are filled with medicamentsduring the manufacturing process. For example, selected reservoirs arefilled with acetaminophen to prevent or attenuate inflammation in theappendix and the colon. The selected reservoirs may each containapproximately 300 nL of acetaminophen solution (e.g., acetaminophen atapproximately 500 mg/ml) and deliver approximately 0.15 mg acetaminophenwhen each reservoir cap is disrupted. Selected reservoirs may be filledwith a different medicament, for example, an antibody to neutralize aproinflammatory cytokine, interferon gamma (see e.g., Hachim et al.,Saudi Med. J. 27:1815-1821, Abstract, 2006 which is incorporated hereinby reference). An antibody fragment (e.g., single chain variable regionfragment, SCFv) that neutralizes gamma interferon is asepticallyinjected into selected reservoirs of the device. Antibody fragments toneutralize a wide variety of antigens are described (see e.g., Pansri etal., BMC Biotechnology 9:6, 2009; available online atbiomedcentral.com/1472-6750/9/6, the subject matter of which isincorporated herein by reference). Methods and materials to createmicrochips with reservoirs containing lyophilized biologicals (e.g.,proteins) are described (see e.g., Farra et al., Sci. Transl. Med. 4,122ra21 (2012) available on lineat:stm.sciencemag.org/content/4/122/122ra21, the subject matter of whichis incorporated herein by reference).

Microelectronic manufacturing methods are used to create thermallyresponsive caps on each reservoir and corresponding resistors forthermal disruption of each reservoir cap and delivery of individualreservoir contents. Microcircuitry connects each reservoir cap to apower source. Methods and materials for constructing arrays ofreservoirs with temperature responsive caps for drug delivery are known(see e.g., U.S. Pat. No. 6,669,683 Ibid.). The device includes amicrobattery to empower the control circuitry and to heat the resistivecircuits in each cap. Rechargeable thin-film microbatteries suitable forintegration with the control circuitry of the implantable device aredescribed (see e.g., U.S. Pat. No. 6,669,683 Ibid.).

The device is anchored by an inflatable collar which expands to attachto the intestinal wall of the appendix when the collar is inflated.Anchors to retain sleeves in the gastrointestinal tract are described(see e.g., U.S. Patent Appl. No. 2013/0281911, which is incorporatedherein by reference). The collar may be cast from silicone and attachedencircling one end of the hexagonal tube. The collar is inflated toapproximately 8-9 mm in diameter once the device is implanted in thelumen of the appendix. The inflatable collar contains an electronicvalve to inflate or deflate the collar. A micro air pump is incorporatedon the device, and control of the valve and air pump is mediated bycontrol circuitry on the device. Control circuitry on the device mayrespond to external signals from a technician, computer, care-giver, orhealthcare worker. For example wireless signals from an externalradiofrequency transmitter, may direct control circuitry to activate theair pump and inflate the collar when the device is implanted in theappendix at the desired location. Conversely internal signals fromsensors on the device may be translated by control circuitry to open thevalve and deflate the collar, thus releasing the device into the lumenof the colon and allowing excretion of the device.

Sensors which detect inflammatory markers (e.g., proinflammatorycytokines and metabolites) near the intestinal wall or in the lumen ofthe colon, send signals to the device control circuitry which areprogrammed to respond by signaling release of anti-inflammatorytherapeutics and/or nutraceuticals into the lumen of the device, oralternatively, to deflate the anchor and release the device into thecolon. For example molecular sensors may detect elevated amounts oftumor necrosis factor (TNF) protein and/or gamma interferon in the lumenof the device and signal the abnormal cytokine levels to controlcircuitry. Sensors that detect proteins and signal electronically may beintegrated into the device along with microfluidic components forsampling intestinal fluids. For example, aptamer-based sensors whichinclude microfluidic components to measure cytokine levels in vivo andreport quantitative results electronically to a computational apparatusare described (see e.g., U.S. Pat. No. 8,145,434, and Maehashi et al.,Anal. Chem. 79:782-787, 2007, each of which is incorporated herein byreference).

The device control circuitry recognizes inflammation, as indicated byelevated levels of inflammatory cytokines, and activates release ofanti-inflammatories (e.g. acetaminophen or anti-gamma interferonantibody) from reservoirs on the device. The dosage and schedule forrelease of anti-inflammatory agents is determined by the controlcircuitry based on the levels of inflammatory markers detected. Forexample, detection of approximately 0.1 ng/mL of gamma interferon inintestinal fluid may trigger release of at least equimolar amounts ofanti-gamma interferon antibodies or antibody fragments (e.g., SCFv), forexample, 0.5-1.0 ng/mL. If advanced inflammation is detected (e.g.highly elevated levels of TNF and/or interferon gamma or clinicalindices such as abdominal pain or an elevated blood neutrophil count)the control circuitry may automatically initiate signaling to deflatethe inflatable collar and release the device into the colon forexcretion. Alternatively, a healthcare worker, the subject itself, oranother party (including a computer programmed for thresholddetermination or response to the device) may signal with a radiofrequency transmitter to the implanted device to initiate deflation ofthe collar and excretion of the device.

In an embodiment, release of a therapeutic or nutraceutical agent from adepot is based on a sensor and pre-determined threshold. For example, ifone or more sensed signals is over a threshold level, the controlelectrical circuitry directs the one or more reservoirs of a depot torelease a therapeutic or nutraceutical agent. In an embodiment, adifferent threshold is set for each reservoir (and may be dictated bythe contents of the reservoir itself, that is for one particulartherapeutic agent a specific threshold is set and for another particulartherapeutic agent a different threshold is set).

The implanted intestinal device may promote a healthy microbiome andassociated GALT by delivering nutraceuticals to the colon. For example,if low or intermediate levels of inflammatory cytokines are detected thecontrol circuitry may signal to reservoirs containing prebiotics whichpromote the growth of beneficial microbes. For example prebiotics, suchas oligofructose and inulin, promote the growth of beneficial bacteria,e.g., Lactobacilli and Bifidobacteria, and stimulate the production ofbutyric acid which reduces inflammation in the colonic mucosa (see e.g.,Damaskos et al., Brit. J. Clin. Pharm. 65:453-467, 2008 which isincorporated herein by reference). Periodic monitoring of inflammatorymarkers by the device sensors informs control circuitry which determinesthe dose and schedule for delivery of prebiotics and anti-inflammatorydrugs. Methods to determine the pharmacokinetics and the dose andschedule of biologicals and pharmaceuticals delivered by implanteddevices are described (see e.g., Farra et al., Ibid.).

Prophetic Example 2 A Semi-Rigid Delivery/Sensory Device withExpandable/Collapsible Anchors for Implantation in the Appendix

A semi-rigid, stent-like device which maintains a flow-through openingin the appendix and provides medicaments and nutraceuticals to theappendix and ascending colon. The device has expandable anchors whichhave collapsible joints (weak points) to allow collapsing the anchorsand removing the device. The device has sensors to detect molecules,microbes and cells in the intestinal fluid and the intestinal wall.Control circuitry on the device receives signals from: the devicesensors, from external sensors, and from external transmitters. Controlcircuitry on the device signals to reservoirs containing medicaments,and to collapsible anchors on the device. The device is manufacturedfrom biocompatible materials and reservoirs are filled withanti-inflammatory agents and prebiotics.

The semi-rigid device is manufactured as a cylindrical tube formed froma grid of polymer struts with an outside diameter of approximately 6 mm.For example a semi-rigid polymer such as polyurethane or polyethylenemay be cast or molded or extruded to form the cylindrical device (seee.g., U.S. Patent Application No. 2014/0012178, which is incorporatedherein by reference). A suitable biocompatible polymer for example,polyethylene-co-vinyl acetate (PEVA) is available from Polysciences,Inc., Warrington, Pa. (see PEVA info sheet incorporated by referenceherein). Methods and materials to manufacture polymers with a desiredporosity and physical properties (e.g., flexibility, tensile strengthand biocompatibility) are described (see e.g., Handbook of MembraneSeparations: Chemical, Pharmaceutical, Food, and BiotechnologicalApplications, edited by Anil K. Pabby, Syed S. H. Rizvi, Ana MariaSastre, 2009, CRC Press, Boca Raton, Fla. which is incorporated hereinby reference). Expandable/collapsible anchors are attached around thecircumference of one end of the device. Stent-like intestinal deviceswith expandable barbs to anchor the device and endoscopic methods toimplant the device are described (see e.g., U.S. Pat. No. 7,267,694,which is incorporated herein by reference).

The semi-rigid cylindrical device and the expandable barb anchors aremanufactured with weak points (see FIG. 2) to allow collapse of the barbanchors and the cylindrical device when removal of the device isdesired. Weak points may be formed from degradable polymers (e.g.,alginate hydrogels or poly lactic-co-glycolic acid) that are composed tobe subject to changes in pH or exposure to chemicals (see e.g., Makadiaet al., Polymers 3:1377-1397, 2011 and Kong et al., Biomacromolecules5:1720-1727, 2004 which are incorporated herein by reference). Or theymay be thin metal strips that melt upon activation of a thermal orelectric pulse (similar to the drug reservoir release caps).

Chemical and enzymatic agents to accelerate degradation at weak pointsmay be acids, bases, or degradative enzymes (e.g., alginase, agarase,esterases). Reservoirs containing degradative chemicals and enzymes areformed adjacent to weak points, and release their contents in responseto signaling from the device control circuitry. For example, clinicalsymptoms may indicate acute appendicitis and a nurse or physician maytransmit a wireless signal to the implanted device to expel the device.Control circuitry on the device receives the expulsion signal andsignals to the reservoirs adjacent to each weak point to releasedegradative chemicals and enzymes. Polymer degradation at the weakpoints and collapse of the barb anchors and the cylindrical devicepromotes expulsion of the device from the appendix and excretion via thecolon. Alternatively, expulsion of the device may be initiated bycontrol circuitry on the device based upon signaling from sensors on theimplanted device.

Sensors which detect inflammatory markers (e.g., proinflammatorycytokines, cells and metabolites) near the intestinal wall or in thelumen of the cecum, send signals to the device control circuitry whichis programmed to respond by signaling release of anti-inflammatorytherapeutics and/or nutraceuticals into the lumen of the device, oralternatively, to initiate expulsion of the device into the colon. Forexample molecular sensors may detect proinflammatory cytokines, tumornecrosis factor (TNF) and/or gamma interferon and electronicallytransmit the cytokine levels to control circuitry. Sensors that detectproteins and cells and signal electronically may be integrated into thedevice along with microfluidic components for sampling intestinalfluids. For example, aptamer-based sensors which include microfluidiccomponents to measure cytokine levels in vivo and report quantitativeresults electronically to a computational apparatus are described (seee.g., U.S. Pat. No. 8,145,434, and Maehashi et al., Anal. Chem.79:782-787, 2007, each of which is incorporated herein by reference).Also aptamer-based sensors may detect leukocytes or bacteria byrecognition of cell surface molecules, e.g., receptors and antigens. Thedevice sensors may monitor molecular and cellular markers ofinflammation over time and quantify changes in the level of cytokines(e.g., TNF, gamma interferon, IL-1) and the number of cells (e.g.,neutrophils) in the appendix and cecum.

Moreover, the device may include an external sensor, to monitorinflammation. An aptamer-based sensor may be implanted intravenously inthe arm of the subject to monitor the neutrophil count over time.Elevated neutrophil numbers in the peripheral blood, indicative ofinflammation, are transmitted wirelessly to the implanted device andreceived by control circuitry on the device. Aptamer based sensors withmicrofluidic components and micro-circuitry to transmit radio frequencysignals are described (see e.g., U.S. Pat. No. 8,145,434 Ibid.). Basedupon sensor input, control circuitry on the implanted device computesthe levels of inflammatory markers and microbes, as well as initiatessignaling to release therapeutics or prebiotics from reservoirs on thedevice.

Reservoirs containing therapeutics, nutraceuticals, chemicals andenzymes are formed on the interior walls of the cylindrical tube.Therapeutics, prebiotics and degradative agents are released into thelumen of the device or adjacent to weak points in the cylindricalstructure and the expandable anchors. Release of agents from thereservoirs is initiated by signaling from control circuitry whichelectronically heats thermally responsive caps on the reservoirs. Thereservoirs are created using microelectronic manufacturing methods andsemiconductor materials.

For example, reservoirs 800 μm×800 μm and approximately 500 μm deep maybe created in silicon wafers using photolithography, chemical etchingand deposition technologies. Hundreds of reservoirs (organized asdepots) may be created in microchips approximately 6 mm×12 mm whichcontain thermally sensitive caps that may be disrupted by electroniccircuitry and embedded resistors. Microelectronic manufacturing methodsare used to create thermally responsive caps on each reservoir andcorresponding resistors for thermal disruption of each reservoir cap anddelivery of individual reservoir contents. Microcircuitry connects eachreservoir cap to a power source. Methods and materials for constructingarrays of reservoirs with temperature responsive caps for drug deliveryare known (see e.g., U.S. Pat. No. 6,669,683, which is incorporatedherein by reference).

The implanted device also includes a microbattery to empower the controlcircuitry and to heat the resistive circuits in each cap. Rechargeablethin-film microbatteries suitable for integration with the controlcircuitry of the implantable device are described (see e.g., U.S. Pat.No. 6,669,683 Ibid.). Methods and materials to create microchips withmultiple reservoirs and thermally sensitive caps are described (seee.g., U.S. Pat. No. 6,669,683 Ibid.). The reservoirs are filled withmedicaments or chemicals during the manufacturing process. For example,selected reservoirs are filled with acetaminophen to prevent orattenuate inflammation in the appendix and the colon. Selectedreservoirs may each contain approximately 300 nL of acetaminophensolution (e.g., acetaminophen at approximately 500 mg/ml) and deliverapproximately 0.15 mg acetaminophen when each reservoir cap isdisrupted. Selected reservoirs may be filled with a differentmedicament, for example, an antibody to neutralize a proinflammatorycytokine, interferon gamma (see e.g., Hachim et al., Saudi Med. J.,27:1815-1821, 2006 which is incorporated herein by reference). Anantibody fragment (e.g., single chain variable region fragment, SCFv)that neutralizes gamma interferon is aseptically injected into selectedreservoirs of the device. Antibody fragments to neutralize a widevariety of antigens are described (see e.g., Pansri et al., BMCBiotechnology 9:6, 2009; available online atbiomedcentral.com/1472-6750/9/6, the subject matter of which isincorporated herein by reference). Methods and materials to createmicrochips with reservoirs containing lyophilized biologicals (e.g.,proteins) are also described (see e.g., Farra et al., Sci. Transl. Med.4, 122ra21 (2012) available on line atstm.sciencemag.org/content/4/122/122ra21, the subject matter of which isincorporated herein by reference).

The implanted intestinal device may promote a healthy microbiome andassociated GALT by delivering nutraceuticals to the colon. For example,if low or intermediate levels of inflammatory cytokines are detected thecontrol circuitry may signal to reservoirs containing prebiotics whichpromote the growth of beneficial microbes. For example prebiotics, suchas oligofructose and inulin, promote the growth of beneficial bacteria,e.g., Lactobacilli and Bifidobacteria, and stimulate the production ofbutyric acid which reduces inflammation in the colonic mucosa (see e.g.,Damaskos et al., Brit. J. Clin. Pharm. 65:453-467, 2008 which isincorporated herein by reference). Periodic monitoring of inflammatorymarkers by the device sensors informs control circuitry which determinesthe dose and schedule for delivery of prebiotics and anti-inflammatorydrugs. Methods to determine the pharmacokinetics and the dose andschedule of biologicals and pharmaceuticals delivered by implanteddevices are described (see e.g., Farra et al., Ibid.).

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. A device, comprising: at least one reversiblyinflatable bladder less than or approximately equal to 10 mm in size; atleast one depot including one or more therapeutic or nutraceutical agentreservoirs; at least one activatable switch operably coupled to at leastone actuator configured to deflate the reversibly inflatable bladderupon activation of the switch; and at least one sensor including one ormore of a camera, ultrasound device, optical sensor, strain sensor,level sensor, or pressure sensor.
 2. The device of claim 1, wherein thereversibly inflatable bladder includes the depot.
 3. (canceled)
 4. Thedevice of claim 1, wherein the reversibly inflatable bladder isconfigured, when at least partially inflated, to secure the devicewithin a lumen of the gastro-intestinal tract of a subject's body. 5.(canceled)
 6. (canceled)
 7. The device of claim 1, wherein activation ofthe switch includes activation by at least one of a timer, externalcommand, or information from the at least one sensor.
 8. The device ofclaim 1, wherein the one or more therapeutic or nutraceutical agentreservoirs include at least one valve.
 9. The device of claim 8, whereinthe at least one valve is operably coupled to control circuitry andconfigured to dispense at least one therapeutic or nutraceutical agentfrom the one or more therapeutic or nutraceutical agent reservoirs. 10.The device of claim 1, wherein each therapeutic or nutraceutical agentreservoir includes a different agent than at least one other agentreservoir.
 11. (canceled)
 12. The device of claim 11, wherein the one ormore therapeutic or nutraceutical agent reservoirs include controlcircuitry directed by at least one of a timer, external command,continuous flow, or signal from at least one internal or externalsensor.
 13. (canceled)
 14. (canceled)
 15. The device of claim 12,wherein the at least one sensor is located in a section of thegastro-intestinal tract of a subject's body.
 16. The device of claim 12,wherein the at least one sensor is located in the subject's body outsideof the gastro-intestinal tract.
 17. The device of claim 12, wherein theat least one sensor is located in a room where the subject is alsolocated.
 18. The device of claim 12, wherein the signal from at leastone sensor represents one or more data from measuring at least one oftemperature, pH, conductivity of fluid, permittivity of fluid, motion,tissue strain, gastro-intestinal tract diameter, inflammation, bacteria,fungi, rate of movement in the gastro-intestinal tract, nutritionalcontent in the gastro-intestinal tract, neoplasia biomarkers, lightscattering in the gastro-intestinal tract, opacity of thegastro-intestinal tract, or presence or concentration of one or moredrug metabolites.
 19. The device of claim 1, further including controlcircuitry operably coupled to at least one of component of the device.20. The device of claim 19, wherein at least one component of the deviceincludes at least one of the depot, actuator, reservoir, switch, sensor,light source, power source, or pump.
 21. The device of claim 1, whereinthe device is configured for at least one of insertion into a subject'sbody or removal therefrom by way of a catheter.
 22. The device of claim21, wherein the device is less than or approximately equal to 9 mm insize, 8 mm in size, 7 mm in size, 6 mm in size, 5 mm in size, 4 mm insize, 3 mm in size, 2 mm in size, 1 mm in size, 900 micrometers, 800micrometers, 700 micrometers, 600 micrometers, 500 micrometers, or anyvalue less than.
 23. (canceled)
 24. The device of claim 1, wherein thedevice includes at least one fin, mobile leg, or revolving belt forself-propulsion.
 25. The device of claim 1, further including at leastone drainage channel continuous with the outer surface of the device.26. The device of claim 25, wherein the at least one drainage channelincludes at least one of a lateral channel, helical channel,longitudinal channel, or interior lumen of the device.
 27. (canceled)28. The device of claim 1, configured for fitting in at least onesection of the gastro-intestinal tract of a subject.
 29. The device ofclaim 28, wherein the at least one section of the gastro-intestinaltract includes at least one of a gastric bypass anastomosis, a gutcavity formed by surgical resection, appendix, cecum, or other section.30. The device of claim 1, further including at least one outer membraneenclosing the reversibly inflatable bladder.
 31. (canceled) 32.(canceled)
 33. (canceled)
 34. (canceled)
 35. The device of claim 1,further including at least one receiver, transmitter, or transceiver.36. The device of claim 35, wherein the at least one receiver is awireless receiver.
 37. The device of claim 35, wherein the at least onetransmitter is a wireless transmitter.
 38. The device of claim 35,wherein the at least one transceiver is a wireless transceiver.
 39. Thedevice of claim 35, wherein the device at least one of transmits orreceives signals relating to status or operation of the depot, at leastone sensed condition, or commands for action of the device.
 40. Thedevice of claim 39, wherein the transmitted or received signalsoriginate or are directed external to the device.
 41. The device ofclaim 1, wherein at least one agent reservoir of the depot isrefillable.
 42. The device of claim 41, wherein the at least onerefillable agent reservoir of the depot includes at least one inlet forrefill of at least one agent by way of catheter, capsule, or pill. 43.The device of claim 1, further including at least one intestinalwall-attachment component.
 44. The device of claim 43, wherein theintestinal wall-attachment component includes at least one of mechanicalor chemical means for attachment to the intestinal wall of a subject.45. The device of claim 43, wherein the intestinal wall-attachmentcomponent includes at least one of a screw, suture, staple, clip,anchor, hook, brace, reversibly inflatable bladder, projection, umbrellaconnector, barb, latch, or adhesive.
 46. (canceled)
 47. (canceled) 48.The device of claim 1, further including a port configured for inflatingthe reversibly inflatable bladder.
 49. The device of claim 1, furtherincluding at least one rigid or semi-rigid frame.
 50. The device ofclaim 49, wherein the rigid or semi-rigid frame includes at least onecollapsible joint.
 51. The device of claim 50, wherein the at least onecollapsible joint is operably coupled to control circuitry.
 52. Thedevice of claim 50, wherein the at least one collapsible joint isoperably coupled to at least one receiver or at least one transmitter.53. (canceled)
 54. A system, comprising: a device including at least onereversibly inflatable bladder less than or approximately equal to 10 mmin size; at least one depot including one or more therapeutic ornutraceutical agent reservoirs; at least one internal or external sensorincluding one or more of a camera, ultrasound device, optical sensor,strain sensor, level sensor, or pressure sensor; and at least oneactivatable switch operably coupled to at least one actuator configuredto deflate the reversibly inflatable bladder upon activation of theswitch; and in operable communication with at least one computingdevice.
 55. (canceled)
 56. (canceled)
 57. The system of claim 54,wherein the at least one sensor is located in a second section of thegastro-intestinal tract of a subject's body.
 58. The system of claim 54,wherein the at least one sensor is located in the subject's body outsideof the gastro-intestinal tract.
 59. The system of claim 54, wherein theat least one sensor is located in a room where the subject is alsolocated.
 60. (canceled)